Beta-Hexosaminidase



Structure of Human β-Hexosaminidase A and its association with Tay-Sachs disease
β-Hexosaminidase A is a lysosomal enzyme essential for the degradation of GM2 gangliosides. Deficiency of lysosomal β-Hexosaminidase A due to inherited defects in the α-subunit gene results in Tay-Sachs (TS) disease. The 3D structure of β-Hexosaminidase A was determined by the group of Michael N.G. James at the University of Alberta, Edmonton, Canada. The structure reveals an αβ-heterodimer, with each subunit having a functional active site. Only the α-subunit active site can hydrolyze GM2 gangliosides due to a flexible loop α280GSEP283 structure that is removed post-translationaly from β, and to the presence of α-Asn 423 and α-Arg 424. The loop structure is involved in binding the GM2 activator protein, while α-Arg424 is critical for binding the carboxylate group of the N-acetyl-neuraminic acid residue of GM2. Two active sites are present in the HexA dimer; one comprising residues from the α-subunit (R178 D207 H262 E323 D322 W373 W392 W460 Y421 R424 N423 E462) and a second one from residues of the β-subunit (R211 D240 H294 E355 D354 W405 W424 Y450 L453 D452 E491 W489). These active sites are located at the opening of TIM barrels at the interface between the α and β-subunits. The HexA undergoes glycosylation on the α and β-subunits; α-Asn 115, α-Asn 157 and α-Asn 295 β-Asn 84, β-Asn 142, β-Asn 190 and β-Asn 327. Mutations in the α-subunit are associated with TS disease and with Late Onset Tay Sachs disease (LOTS) (Chronic  & Acute  clinical phenotype). Interestingly, α-G269S is the most common mutation associated with LOTS disease.

3D Structures of Beta-Hexosaminidase
2xpk, 2w1n – CpBHEXB – Clostridium perfringens

2o4e – CpBHEXB - NMR

2v5c, 2v5d – CpBHEXB catalytic domain

2jh2 – CpBHEXB cohesin-like module

3gh4 – PaBHEX – Paenibacillus

3bmx – BHEX – Bacillus subtilis

1tr9 – VcBHEX – Vibrio cholerae

1hp4 – SpBHEX – Streptomyces plicatus

1qba – SmBHEX – Serratia marcescens

3lmy, 1o7a, 1nou – hBHEXB β subunit – human

1o7a - hBHEXB β subunit

2gjx - hBHEXA α+β subunits

Binary complexes
2gk1 - hBHEXA α+β subunits + NGT

1now - hBHEXB β subunit + GalNAc-isofagomine

1np0 - hBHEXB β subunit + intermediate analog

3gh5, 3gh7 - PaBHEX + GlcNAc

1m01 - SpBHEX + GlcNAc

1m03, 1m04 - SpBHEX (mutant) + GlcNAc

1jak - SpBHEX + inhibitor

1hp5 - SpBHEX + intermediate analog

2x0y, 2wb5, 2vur - CpBHEXB + inhibitor

2ozn – CpBHEXB + hyaluronidase

3nsm – OfBHEX residues 23-594 – Ostrinia furnacalis

3nsn - OfBHEX residues 23-594 + chitotriomycin

2xj7 – BtBHEXB + castanospermine – Bacteroides thetaiotaomicron

2wzh, 2wzi - BtBHEXB (mutant) + oxazoline

2vvn - BtBHEX + thiazoline

2x0h - BtBHEXB Michaelis complex

2wca, 2vvs - BtBHEX + PUGNAc

2w66, 2w67, 2w4x, 2jiw – BtBHEXB + inhibitor

3gs6, 3gsm, 2oxn - VcBHEX + PUGNAc

1y65 - VcBHEX + NAG

1c7s – SmBHEX + diNAG

1c7t - SmBHEX (mutant) + diNAG